A Study on the Effect of Tazemetostat (study drug) in Pediatric Subjects withwith relapsed or refractory Tumors or Synovial Sarcoma

Phase 1

• Conditions: Atypical teratoid rhabdoid tumor (ATRT), Malignant rhabdoid tumor (MRT), Rhabdoid tumor of kidney (RTK), selected tumors with rhabdoid features.Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, Extraskeletal myxoid chondrosarcoma, Myoepithelial carcinoma, Renal medullary carcinoma, Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval, Synovial Sarcoma with a SS18-SSX rearrangement; MedDRA version: 21.1Level: LLTClassification code 10064886Term: Renal medullary carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10065870Term: Atypical teratoid/rhabdoid tumor of CNSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10073134Term: Extraskeletal myxoid chondrosarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10073335Term: Rhabdoid tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10074121Term: Rhabdoid tumor of the kidneySystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10042863Term: Synovial sarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: HLTClassification code 10015100Term: Epithelioid sarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-002468-18-GB
• Lead Sponsor: Epizyme, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2015-10-29
• Last Update Posted: 8 June 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

1.Age (at the time of consent/assent): =12 months to <18 years
Cohort 4 only: =10 years to <18 years
2.Performance Status:
If <12 years of age: Lansky Performance Status >50%
If =12 years of age: Karnofsky Performance Status >50%
3.Has provided signed written informed consent/assent
4. Life expectancy of >3 months
5.Has relapsed or refractory disease and no standard treatment options
6.Is ineligible or inappropriate for other treatment regimens known to have effective potential
7.Has a documented local diagnostic pathology of original biopsy
8.Has all prior treatment related clinically significant toxicities resolve to = Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant
9.Prior therapy(ies) must be completed according to the protocol.
10.Has adequate hematologic BM & coagulation factors, renal & hepatic function as defined by criteria in the protocol
11.Specific requirements for subjects with CNS involvement eg: stable deficits within certain timeframe, stable seizure, treated brain metastases without evidence of progression
12.Has a LV fractional shortening of >27% or an LV ejection fraction of =50% by ECHO or MUGA scan & NYHAC =2.
13. Has a QT interval corrected by Fridericia's formula (QTcF) =450 msec.
14.Is able to swallow and retain orally administered medication and does not have any uncontrolled GI condition that may alter absorption
15.Has sufficient tumor tissue for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis
16.Is willing and able to comply with all aspects of the protocol as judged by investigator
17.18. For female subjects of childbearing potential and for male subjects with a female partner of childbearing potential Subject must adhere to contraception methods described in the protocol
For Dose Escalation Only:
ALL criteria above for all subjects and the following:
1.Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination or and other lesions such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis or hepatosplenomegaly from disease
2.Has one of the following histologically confirmed tumors: Rhabdoid tumor: ATRT, MRT, RTK, selected tumors with rhabdoid features, INI1-negative tumor: (Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, EMC, Myoepithelial carcinoma, Renal medullary carcinoma), other INI1-negative malignant tumors, Synovial sarcoma with SS18-SSX rearrangement
3. For subjects with ATRT, MRT, and RTK or tumors with rhabdoid features only: the following test results must be available:
•Morphology and immunophenotypic panel consistent with rhabdoid tumor, and
•Loss of INI1 or SMARCA 4 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 or SMARCA 4 loss or mutation when INI1 or SMARCA 4 IHC is equivocal or unavailable
4. For subjects with INI1 negative tumor only the following test results must be available:
•Morphology and immunophenotypic panel consistent with INI1 negative tumors, and
•Loss of INI1 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable
5.For subjects with synovial sarcoma with SS18-SSX rearangement only the following test results must be available:
•Morphology consistent with synovial sarcoma, and
•

Exclusion Criteria

1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homolog2 (EZH2).
2.Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy.
3.Has participated in another interventional clinical study and received investigational drug within 30 days or five half-lives, whichever is longer, prior to the planned first dose of tazemetostat.
4.Has had major surgery within 2 weeks prior to enrolment
5. Has thrombocytopenia, neutropenia, or anemia of Grade =3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing. Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central lab at screening. Cytogenetic testing and DNA sequencing.
Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment at Screening. Cytogenetic testing and DNA sequencing will be conducted by a central laboratory following an abnormal result of bone marrow aspirate/biopsy.
6. Has a prior history of T-LBL/T-ALL.
7.Has clinically active heart disease including prolonged QTcF QTcF (>450 msec).
8. Is currently taking any prohibited medication(s) as described in section 7.3.
9.Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study.Has an active infection requiring systemic treatment.
10.Has an active infection requiring systemic treatment.
11.Is immunocompromised (ie congenital immunodeficiency), including subjects with a known history of infection with human immunodeficiency virus (HIV).
12.Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA).
13.Has had a symptomatic venous thrombosis within 14 days prior to study enrollment.
14.For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents.
15.Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben.
16.Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements.
17.For female subjects of childbearing potential: Is pregnant or nursing.
For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 3 monts after last dose of tazemetostat.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified